4-6270040-G-GGCGCGGTGGCTGTGGGCA

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_006005.3(WFS1):c.-6+32_-6+49dup variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 152,020 control chromosomes in the GnomAD database, including 4,631 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.21 (4630 hom., cov: 29)
  • Exomes 𝑓: 0.081 (1 hom.)
• Consequence: WFS1 NM_006005.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.74

Genes affected

WFS1 (HGNC:12762): (wolframin ER transmembrane glycoprotein) This gene encodes a transmembrane protein, which is located primarily in the endoplasmic reticulum and ubiquitously expressed with highest levels in brain, pancreas, heart, and insulinoma beta-cell lines. Mutations in this gene are associated with Wolfram syndrome, also called DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness), an autosomal recessive disorder. The disease affects the brain and central nervous system. Mutations in this gene can also cause autosomal dominant deafness 6 (DFNA6), also known as DFNA14 or DFNA38. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP6: Variant 4-6270040-G-GGCGCGGTGGCTGTGGGCA is Benign according to our data. Variant chr4-6270040-G-GGCGCGGTGGCTGTGGGCA is described in ClinVar as [Benign]. Clinvar id is 1233567.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.401 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WFS1	NM_006005.3	c.-6+32_-6+49dup		intron_variant		ENST00000226760.5
WFS1	NM_001145853.1	c.-2+32_-2+49dup		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WFS1	ENST00000226760.5	c.-6+32_-6+49dup		intron_variant		1	NM_006005.3	P2

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32117 AN: 151824 Hom.: 4612 Cov.: 29

Gnomad AFR AF: 0.405

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.157

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.0637

Gnomad SAS AF: 0.184

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.185

GnomAD4 exome AF: 0.0814 AC: 7 AN: 86 Hom.: 1 Cov.: 0 AF XY: 0.106 AC XY: 7 AN XY: 66

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 NFE exome AF: 0.0658

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.212 AC: 32172 AN: 151934 Hom.: 4630 Cov.: 29 AF XY: 0.208 AC XY: 15482 AN XY: 74260

Gnomad4 AFR AF: 0.406

Gnomad4 AMR AF: 0.157

Gnomad4 ASJ AF: 0.152

Gnomad4 EAS AF: 0.0627

Gnomad4 SAS AF: 0.183

Gnomad4 FIN AF: 0.115

Gnomad4 NFE AF: 0.138

Gnomad4 OTH AF: 0.185

Alfa AF: 0.166 Hom.: 247

Asia WGS AF: 0.156 AC: 542 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 15, 2018

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs71528898; hg19: chr4-6271767;